1. Field of the Invention
The present invention relates to the field of photodynamic therapy, particularly to formulations for improved photodynamic therapy.
2. Information Disclosure Statement
Photodynamic therapy (PDT) has become an increasingly prevalent treatment option for a variety of diseases characterized by hyperproliferative cells, such as cancer and certain skin conditions such as psoriasis. Hyperproliferative epithelial diseases (epidermal and mucosal diseases) are a major health problem and affect nearly everyone at least once during his or her lifetime. Other examples of hyperproliferative epithelial diseases include cutaneous tumors (basal cell carcinoma, squamous cell carcinoma, melanoma), Barrett's esophagus, virus-caused diseases (warts, herpes simplex, condylomata acuminata), premalignant and malignant diseases of the female genital tract (cervix, vagina, vulva), and premalignant and malignant diseases of mucosal tissues (oral, bladder, rectal).
PDT uses photosensitizers (PS) in combination with light irradiation at specific wavelengths to induce oxidative damage in hyperproliferative cells and tissues. It is thought that hyperproliferative tissues selectively retain PS and that subsequently induced cell damage is localized in areas of PS accumulation. Numerous types of photosensitizers have been evaluated and shown to be at least partially effective for PDT. Known PDT photosensitizers include psoralens, porphyrins, chlorins, bacteriochlorins, pheophorbide, bacteriopheophorbide and phthalocyanins, as well as precursors to protoporphyrin IX such as 5-AminoLevulinic Acid (ALA).
In large part, the efficacy of PDT treatment depends on the photochemical, photobiological, and pharmacokinetic/phototherapeutic properties of the photosensitizer (PS). Consequently, the formulation of the PS is a critical factor in the successful photodynamic treatment of hyperproliferative disease. To be therapeutically useful, a PS formulation should deliver the PS in a form that can be readily and selectively internalized by hyperproliferative target cells, while also facilitating accurate and convenient dosing. Known photodynamic medicaments are administered or dosed in milligram quantities relative to kilograms of body weight (mg/kg), however, sub-milligram PS dosing has been proposed for specific vascular treatments and to stimulate wound healing. But, for the treatment of cancerous tissues, it is believed that a similar low dose regime would reduce the effectiveness of PDT, especially for treatments where the PS is administered systemically. As used herein, “low concentration formulation” is defined as a formulation with a substantially reduced PS concentration as compared to known PDT formulations and medicaments. Similarly, “low concentration therapy” refers to any PDT treatment method that administers photosensitizers in a low concentration formulation.
Meta-tetra(hydroxyphenyl)chlorin (“m-THPC”), also known as Temoporfin and by the trade name Foscan®, is a photosensitizer shown to be effective in PDT of cancer, especially for advanced head and neck squamous cell carcinoma. The recommended dose for m-THPC is 0.15 mg/kg of body weight, and is provided in a 4 mg/ml solution for administration via intravenous injection.
Some other commonly used porphyrins for photodynamic therapy are Hematoporphyrin IX (HpIX), Hematoporphyrin derivative (HpD) and various HpD preparations such as Photofrin® (porfimer sodium, Axcan Pharma PDT Inc.). For the treatment of esophageal cancer and endobronchial non-small cell cancer, Photofrin® has a recommended dose of 2 mg/kg of body weight, which is administered by injection after reconstituting dried Photofrin® in a 2.5 mg/ml solution. Photogem®, another hematoporphyrin derivative, has a recommended dose of 1-2 mg/kg of body weight, which is administered by injection from a 5 mg/ml stock solution.
However, known photodynamic medicaments suffer from the relatively unselective uptake and retention of the PS by hyperproliferative cells, which results in the destruction of normal tissues during the PDT irradiation cycle. Furthermore, high concentration PS formulations increase the incidence, severity, and duration of side effects such as generalized post-treatment skin and eye photosensitivity, as well as treatment site irritation and pain.
The general photosensitization of the skin and eyes after treatment with PS is a well documented side-effect of conventional photodynamic therapy, and is especially common in PDT methods requiring the systemic administration of photosensitizers. After such treatments, the patient experiences a generalized skin photosensitivity which creates the risk of a widespread and severe erythema (skin redness) if the patient is exposed to visible light. In treatment regimes where photosensitizers are topically applied, the treatment area will remain photosensitized for 6 weeks or more. During any period of general or local photosensitivity, patients must avoid sunlight and bright indoor light to allow the photosensitizer to clear from the skin and blood stream. Patients must also wear protective clothing and sunglasses when outdoors.
Another side-effect associated with conventional PDT treatment, is injection site irritation and pain. It is very common for patients to experience a burning feeling or other unpleasant sensations at the site of PS injection during the administration of photodynamic medicaments. Other known post-treatment complications at the site of PS administration include phlebitis, lymphangitis and chemical burns. Although PDT is much less traumatic than other cancer treatments, including chemotherapy and certain radiation therapies, a convenient and cost-effective strategy for reducing the incidence and/or severity of PDT specific side-effects is needed.
U.S. Pat. Nos. 4,992,257 and 5,162,519 disclose the use of select dihydro-porphyrins and tetrahydro porphyrins, including m-THPC, in combination with light irradiation (652-653 nm) to induce necrosis (tissue death) in tumors. In particular, these references describe the depth of tumor necrosis that results when m-THPC is dosed at 0.5 mg/kg as compared to 0.255 mg/kg. Specifically, these references teach that the depth of tumor necrosis increases by 43% when m-THPC is administered at the higher dose (5.41±0.39 mm and 3.79±0.28 mm, respectively).
U.S. Pat. No. 6,609,014 describes a “low dose PDT” method limited to the treatment of restenosis and intimal hyperplasia in blood vessels. The reference defines “low dose PDT” as a total photodynamic experience at substantially lower levels of intensity than ordinarily employed and teaches a method comprised of three variables, namely photosensitizer concentration, light dose and time of irradiation. Moreover, the reference teaches that an increase in one variable permits a decrease in another. As such, this reference does not teach the effect of photosensitizer dose outside and independent from changes in irradiation dose or other parameters. Nor does this reference teach the significance of photosensitizer concentration in the context of treating other hyperproliferative tissues or cell types with PDT.
U.S. Pat. No. 5,399,583 discloses a limited group of hydro-monobenzoporphyrins, or “green porphyrins,” which are photoactive at wavelengths of 670-780 nm. This wavelength of light is thought to penetrate deeper into body tissues which may allow for the use of lower doses of green porphyrins in PDT. Further, this reference discloses doses ranging from 0.1 mg/kg to 10 mg/kg for the claimed green porphyrin compounds, but does not describe the effect of photosensitizer concentration for this or other classes of photo sensitizers.
The prior art described above does not teach nor anticipate the impact of reducing photosensitizer concentration on cytotoxicity. Moreover, there remains a need for PS formulations that are more efficient and have fewer and/or less severe side-effects than known PDT methods and formulations. The present invention addresses these needs.